WO2013138600A1 - Composés radioprotecteurs - Google Patents

Composés radioprotecteurs Download PDF

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Publication number
WO2013138600A1
WO2013138600A1 PCT/US2013/031385 US2013031385W WO2013138600A1 WO 2013138600 A1 WO2013138600 A1 WO 2013138600A1 US 2013031385 W US2013031385 W US 2013031385W WO 2013138600 A1 WO2013138600 A1 WO 2013138600A1
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substituted
unsubstituted
compound
dim
pharmaceutically acceptable
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PCT/US2013/031385
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English (en)
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Eliot M. Rosen
Milton Brown
Saijun Fan
Thomas Walls
Kathryn Sheikh
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Rosen Eliot M
Milton Brown
Saijun Fan
Thomas Walls
Kathryn Sheikh
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Application filed by Rosen Eliot M, Milton Brown, Saijun Fan, Thomas Walls, Kathryn Sheikh filed Critical Rosen Eliot M
Priority to US14/385,575 priority Critical patent/US10266490B2/en
Publication of WO2013138600A1 publication Critical patent/WO2013138600A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092—Details
    • A61N2005/1094—Shielding, protecting against radiation

Definitions

  • Radioprotector agents are used in diagnostic and therapeutic settings to protect normal (e.g., non-cancerous) tissues or structures from radiation damage. These agents are also used as a means of protection in the setting of radiation exposure to the normal population.
  • current commercially available radioprotectors are generally too toxic or are insufficiently active to be clinically useful.
  • radioprotector compounds Also provided herein are methods for their use in reducing or preventing radiation damage in a subject, killing a tumor cell and protecting a non-tumor cell, and treating cancer in a subject.
  • a class of compounds described herein includes compounds of the following structure:
  • L is -CH 2 - or -
  • R 1 and R 2 are each independently selected from hydrogen, substituted or
  • a class of com ounds described herein includes compounds of the following structure:
  • R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbonyl, or substituted or unsubstituted sulfonyl;
  • R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbonyl,
  • Exemplary compounds according to this structure include:
  • n is 1, 2, or 3;
  • R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted carboxyl;
  • R 5 is hydrogen or substituted or unsubstituted sulfonyl;
  • R 6 is hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstitute
  • a class of compounds described herein includes compounds of the following structure:
  • R 1 is substituted or unsubstituted aryl; and R 2 , R 3 , and R 4 are each independently selected from hydrogen, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • compositions comprising one or more compounds described above and a pharmaceutically acceptable carrier.
  • a method of reducing or preventing radiation damage in a subject includes administering to the subject an effective amount of a compound or composition as described herein.
  • the method can further include administering a second therapeutic agent, such as a radioprotector compound or 3,3 '-diindolylmethane (DIM) to the subject.
  • a second therapeutic agent such as a radioprotector compound or 3,3 '-diindolylmethane (DIM)
  • a method of reducing radiation damage in a subject includes administering to the subject an effective amount of 3,3 '-diindolylmethane (DIM) or analog thereof after exposure of the subject to radiation.
  • the DIM or analog thereof is administered to the subject at least 24 hours after exposure of the subject to radiation.
  • a method of reducing or preventing radiation damage in a subject includes administering to the subject an effect amount of 3,3'- diindolylmethane (DIM) or analog thereof, wherein the DIM or analog thereof is
  • the DIM or analog thereof is administered in multiple doses.
  • a method of killing a tumor cell and protecting a non-tumor cell includes irradiating the tumor cell with an effective amount of ionizing radiation and administering to the non-tumor cell an effective amount of 3,3'-diindolylmethane (DIM), an effective amount of a compound or composition described herein, or a combination thereof.
  • the irradiating step can be performed prior to the administering step.
  • the administering step can be performed prior to the irradiating step.
  • the method is performed in vivo.
  • the method is performed in vitro.
  • the tumor cell can be a BRCAi -deficient tumor cell.
  • a method of treating cancer in a subject includes administering to the subject an effective amount of ionizing radiation and administering to the subject an effective amount of 3,3 '- diindolylmethane (DIM), an effective amount of a compound or composition described herein, or a combination thereof.
  • the cancer is breast cancer (e.g., BRCAi - deficient breast cancer) or ovarian cancer (e.g., BRCAi -deficient ovarian cancer).
  • Fig. 1 is a graph demonstrating the percentage of survival for rats that were exposed to total body irradiation and were treated with DIM.
  • Fig. 2 contains graphs demonstrating the percentage of survival for rats that were exposed to different doses of total body irradiation (RT), with and without DIM treatment.
  • Panel A shows the results for rats exposed to 13-Gy of ⁇ -rays and then given once daily doses of DIM (as indicated) for 14-days, with the first administration 10-min after RT.
  • Panels B and C show the results for rats exposed to different doses of RT and then given once daily doses of DIM (75 mg/kg) for 14-days, with the first administration 10-min after RT.
  • Panel D shows the results for rats given a 13-Gy dose of RT and having DIM (75 mg/kg) administered starting at different times post total body irradiation, as indicated.
  • DIM was administered by intraperitoneal (ip) injection with physiological saline as the vehicle and control animals were irradiated but received injections of saline only. Survival was plotted by Kaplan Meier method.
  • Figs. 3A, 3B, and 3C show that DIM protects against different doses of total body radiation when administered starting 24-hr after irradiation.
  • Fig. 4 contains data showing that DIM does not protect MDA-MB-231 tumor xenografts grown in athymic nude mice against fractionated radiation.
  • Panel B contains Western blots of athymic nude mice containing MDA-MB-231 xenograft tumors grown in the mammary fat pads treated without (-) or with (+) a single dose of DIM (75 mg/kg) at different times before or after irradiation and then received 20-Gy of ⁇ -rays.
  • Panel C contains Western blots for the mice treated or not treated with DIM (75 mg/kg) at the indicated time before or after total body irradiation (TBI, 20-Gy).
  • SI 988 in rat ATM corresponds to SI 981 in human ATM.
  • FIG. 5 contains Western blots showing that DIM activates ATM in vivo.
  • Figure 5A shows Sprague-Dawley rats treated without (-) or with (+) DIM (75 mg/kg) 24-hr before sham-treatment (-) or TBI (+).
  • Figure 5B shows rats treated without (-) or with (+) DIM (75 mg/kg) 1-hr before sham-treatment (-) or TBI (+).
  • Figure 5C shows rats sham-treated (-) or treated with TBI (20-Gy) (+) and administered vehicle (-) or DIM (+) at 10-min after radiation.
  • Phospho-ATM (serine-1988) in rat corresponds to phospho-ATM (serine-1981) in humans.
  • Fig. 6 contains graphs demonstrating the radioprotection of cultured human cells by DIM.
  • Panels A and B show the surviving fraction of subconfluent proliferating cultures of 184A1 (Panel A) and Hs578Bst (Panel B) cells pre-treated with DIM (0.3 ⁇ ) or vehicle (DMSO) for 24-hr and irradiated using different doses of ⁇ -rays.
  • Panels C and D show the concentration dependence of DIM radioprotection on clonogenic survival of 184A1 (Panel C) and Hs578Bst (Panel D) cells using a single dose of radiation (8-Gy) and different concentrations of DIM.
  • Fig. 7 shows that DIM rapidly causes ATM activation and subsequent
  • Figure 7A contains Western blots of subconfluent proliferating 184A 1 human mammary epithelial cells exposed to DIM (0.3 ⁇ ) for different time intervals. Phosphorylated or total levels of ATM and of several different ATM substrate proteins were determined, as indicated. As a negative control, cells were treated with a selective inhibitor of ATM kinase activity (KU55933).
  • Figure 7B contains Western blots of 184A1 cells either untreated or treated with radiation (2-Gy of ⁇ - radiation) and/or DIM (0.3 ⁇ ).
  • Fig. 8 contains a Western blot of subconfluent proliferating 184A1 human mammary epithelial cells exposed to DIM (0.3 ⁇ ) for different time intervals. Phosphorylated or total levels of ATM and of different DNA damage-response proteins were determined, as indicated.
  • FIG. 9 shows that ATM and BRCA1 are required for radioprotection by DIM.
  • Panel A depicts the clonogenic survival of 184A1 human mammary epithelial cells pre-treated with control-siR A or ATM-siRNA (50 nM for 48-hr), treated ⁇ DIM (0.3 ⁇ ) for 24-hr, and irradiated. The extent of knockdown of ATM is shown in the inset Western blot.
  • Panels B and C show the clonogenic survival of ATM-competent (+/+) MRC5 human fibroblasts (Panel B) or ATM mutant (-/-) AT5 human fibroblasts (Panel C) pre-treated ⁇ DIM (1 ⁇ ) for 24-hr and irradiated.
  • the Western blot inset in Panel C shows the ATM protein levels in MRC5 and AT5 fibroblasts.
  • Panel D shows BRCA1 -competent (Brcal +/+) or BRCA1- deficient (Brcal-/-), but otherwise isogenic, mouse embryo fibroblasts pre-treated ⁇ DIM (0.3 ⁇ ) for 24-hr and then assayed for clonogenic survival in response to radiation.
  • Fig. 10 shows that DIM protects wild-type but not Mrel 1 mutant human dermal fibroblasts.
  • Panels A, B, and C show subconfluent proliferating wild-type (CWAT) (Panel A) or Mrel 1 mutant (ATLD2 (Panel B) and ATLD3 (Panel C)) human skin fibroblasts treated with DIM (0.3 ⁇ ) or vehicle (DMSO) for 24-hr; irradiated with different doses of 137 Cs ⁇ -rays; and harvested for clonogenic survival assays.
  • Cell survival values are means ⁇ SEMs of three replicate dishes.
  • Panel D shows Western blots of wild-type or Mre-11 mutant (ATLD2) fibroblasts treated with DIM (0.3 ⁇ ) or vehicle for 30 min and then subjected to Western blotting to detect phospho-ATM (S 1981), total ATM, phospho-BRCA 1 (S 1387), total BRCA1, or actin (loading control).
  • ATLD2 wild-type or Mre-11 mutant
  • FIG. 11 shows that DIM stimulates DNA repair and inhibits apoptosis.
  • Figures 11 A and 1 IB show subconfluent proliferating 184A1 (Figure 1 1A) or Hs578Bst (Figure 1 IB) cells pre-treated ⁇ DIM (0.3 ⁇ x 24 hr); exposed to radiation (3-Gy) on ice; and subjected to neutral comet assays at different times post- irradiation.
  • Values of % tail DNA are means ⁇ ranges of two determinations.
  • Figure 11C shows plasmid strand-rejoining assays carried out using 75 ⁇ g of nuclear lysates from 184A1 cells that were treated with DIM (0.3 ⁇ ) or vehicle (DMSO) for 24-hr with and without ATM kinase inhibitor KU55933 (10 ⁇ ).
  • Panel D shows the apoptosis assays of 184A1 cells pre-treated ⁇ DIM (0.3 ⁇ ) for 24-hr and irradiated with 6-Gy of ⁇ -rays. At 24-hr after irradiation, cells were analyzed by flow cytometry for apoptosis, by measuring membrane redistribution of phosphatidylserine. The percentage of early and late apoptotic cells for non-irradiated control cells were: vehicle treated, 1.25% and 1.34%, and DIM-treated, 0.54% and 1.02%, respectively.
  • Fig. 12 contains graphs depicting the clonogenic survival curves of non-tumorigenic human mammary epithelial cell lines Hs5788st after different doses of gamma ray irradiation, with and without KED-4-69 treatment (top left panel), KED-4-46 treatment (top right panel), KED-4-123 treatment (bottom left panel), and THW-5-85 treatment (bottom right panel).
  • Fig. 13 contains graphs depicting the clonogenic survival curves of non-tumorigenic human mammary epithelial cell lines Hs5788st after a single dose of gamma ray irradiation, with and without DIM treatment (panel A; top left panel), THW-5-85 treatment (panel B; top right panel), KED-4-155 treatment (panel C; bottom left panel), and KED-4-157 treatment (panel D; bottom right panel).
  • Described herein are compounds for use as radioprotectors. Also provided herein are methods for their use. Such methods include reducing or preventing radiation damage in a subject, killing a tumor cell and protecting a non-tumor cell, and treating cancer in a subject. The methods of reducing or preventing radiation damage in a subject, killing a tumor cell and protecting a non-tumor cell, and treating cancer in a subject described herein include administering to the subject one or more radioprotector compounds.
  • a class of radioprotector compounds useful in the methods described herein includes compounds represented by Formula I:
  • R 1 and R 2 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted carbonyl.
  • R 1 and R 2 can optionally combine to form a heterocycle or heteroaryl.
  • Examples of Formula I include the following compounds:
  • a class of radioprotector compounds useful in the methods described herein includes compounds represented by Formula II:
  • R 1 and R 4 are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbonyl, or substituted or unsubstituted sulfonyl.
  • R 1 is methyl.
  • R 4 is dansyl or benzyl.
  • R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted sulfonyl.
  • R 2 is hydrogen.
  • R 3 and R 5 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted carboxyl.
  • R 3 is methyl and R 5 is hydrogen.
  • R 3 is hydrogen and R 5 is methyl.
  • R 1 is methyl
  • R 2 is H
  • R 3 is H
  • R 5 is methyl
  • R 4 is not dansyl
  • Examples of Formula II include the following compounds:
  • the compound of Formula II is not Compound II-2.
  • a class of radioprotector compounds useful in the methods described herein includes compounds represented by Formula III:
  • n is 1, 2, or 3.
  • n is 1.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted carboxyl.
  • R 1 , R 2 , R 3 , and R 4 are each hydrogen.
  • R 1 , R 2 , R 3 , or R 4 can be pegylated (e.g., -OPEG).
  • R 5 is hydrogen or substituted or unsubstituted sulfonyl.
  • R 5 is hydrogen, tosyl, or dansyl.
  • R 6 is hydrogen, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloheteroalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted cycloheteroalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbonyl, substituted or unsubstitute
  • each R 7 is hydrogen or substituted or unsubstituted alkyl.
  • Examples of Formula III include the following compounds:
  • Formula III can be represented by Formula III-A:
  • R 6 is selected from hydrogen or one of the following structures:
  • Formula III can be represented by Formula III-B: III-B
  • R 6 is selected from hydrogen or one of the following structures:
  • Formula III can be represented by Formula III-C:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, fluoro, chloro, methoxy, phenyl, trifluoromethyl, and
  • Formula III can be represented by Formula III-D:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected from hydrogen, fluoro, chloro, methoxy, phenyl, trifluoromethyl, and dimethylamino.
  • R 8 is dimethylamino.
  • a class of radioprotector compounds useful in the methods described herein includes compounds represented by Formula IV:
  • R 1 is substituted or unsubstituted aryl.
  • R 2 , R 3 , and R 4 are each independently selected from hydrogen and substituted or unsubstituted aryl or heteroaryl.
  • a compound useful in the methods described herein includes 3,3'-diindolylmethane (DIM) as shown below:
  • the DIM is microencapsulated.
  • alkyl, alkenyl, and alkynyl include straight- and branched- chain monovalent substituents. Examples include methyl, ethyl, isobutyl, 3-butynyl, and the like. Ranges of these groups useful with the compounds and methods described herein include C1-C20 alkyl, C2-C20 alkenyl, and C2-C20 alkynyl.
  • Additional ranges of these groups useful with the compounds and methods described herein include C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkyl, C2-C4 alkenyl, and C2-C4 alkynyl.
  • Heteroalkyl, heteroalkenyl, and heteroalkynyl are defined similarly as alkyl, alkenyl, and alkynyl, but can contain O, S, or N heteroatoms or combinations thereof within the backbone. Ranges of these groups useful with the compounds and methods described herein include C1-C2 0 heteroalkyl, C2-C2 0 heteroalkenyl, and C2-C2 0 heteroalkynyl.
  • Additional ranges of these groups useful with the compounds and methods described herein include Ci- C12 heteroalkyl, C2-C12 heteroalkenyl, C2-C12 heteroalkynyl, C1-C6 heteroalkyl, C2-C6 heteroalkenyl, C2-C6 heteroalkynyl, C1-C4 heteroalkyl, C2-C4 heteroalkenyl, and C2-C4 heteroalkynyl.
  • cycloalkyl, cycloalkenyl, and cycloalkynyl include cyclic alkyl groups having a single cyclic ring or multiple condensed rings. Examples include cyclohexyl, cyclopentylethyl, and adamantanyl. Ranges of these groups useful with the compounds and methods described herein include C3-C20 cycloalkyl, C3-C20 cycloalkenyl, and C3-C20 cycloalkynyl.
  • Additional ranges of these groups useful with the compounds and methods described herein include C5-C12 cycloalkyl, C5-C12 cycloalkenyl, C5-C12 cycloalkynyl, C5-C6 cycloalkyl, C5-C6 cycloalkenyl, and C5-C6 cycloalkynyl.
  • heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl are defined similarly as cycloalkyl, cycloalkenyl, and cycloalkynyl, but can contain O, S, or N
  • Ranges of these groups useful with the compounds and methods described herein include C3-C2 0 heterocycloalkyl, C3-C2 0 heterocycloalkenyl, and C3-C2 0 heterocycloalkynyl. Additional ranges of these groups useful with the compounds and methods described herein include C5-C12 heterocycloalkyl, C5-C12 heterocycloalkenyl, C5-C12 heterocycloalkynyl, C5-C6 heterocycloalkyl, C5-C6 heterocycloalkenyl, and C5-C6 heterocycloalkynyl.
  • Aryl molecules include, for example, cyclic hydrocarbons that incorporate one or more planar sets of, typically, six carbon atoms that are connected by delocalized electrons numbering the same as if they consisted of alternating single and double covalent bonds.
  • An example of an aryl molecule is benzene.
  • Heteroaryl molecules include substitutions along their main cyclic chain of atoms such as O, N, or S. When heteroatoms are introduced, a set of five atoms, e.g., four carbon and a heteroatom, can create an aromatic system. Examples of heteroaryl molecules include furan, pyrrole, thiophene, imadazole, oxazole, pyridine, and pyrazine.
  • Aryl and heteroaryl molecules can also include additional fused rings, for example, benzofuran, indole, benzothiophene, naphthalene, anthracene, and quinoline.
  • the aryl and heteroaryl molecules can be attached at any position on the ring, unless otherwise noted.
  • heterocycloalkynyl molecules used herein can be substituted or unsubstituted.
  • substituted includes the addition of an alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl group to a position attached to the main chain of the alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl, e.g., the replacement of a hydrogen by one of these molecules.
  • substitution groups include, but are not limited to, hydroxyl, halogen (e.g., F, Br, CI, or I), and carboxyl groups.
  • halogen e.g., F, Br, CI, or I
  • carboxyl groups e.g., but are not limited to, hydroxyl, halogen (e.g., F, Br, CI, or I), and carboxyl groups.
  • the term unsubstituted indicates the alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, or heterocycloalkynyl has a full complement of hydrogens, i.e., commensurate with its saturation level, with no substitutions, e.g., linear decane (-(CH 2 )9
  • the compounds described herein or derivatives thereof can be provided in a pharmaceutical composition.
  • the pharmaceutical composition can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, or suspensions, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include a therapeutically effective amount of the compound described herein or derivatives thereof in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, or diluents.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, which can be administered to an individual along with the selected compound without causing unacceptable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained.
  • the term carrier encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations.
  • a carrier for use in a composition will depend upon the intended route of administration for the composition.
  • the preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in
  • physiologically acceptable carriers include buffers, such as phosphate buffers, citrate buffer, and buffers with other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and/or nonionic surfactants, such as TWEEN ® (ICI, Inc.; Bridgewater, New Jersey), polyethylene glycol (PEG), and PLURONICSTM (BASF; Florham Park,
  • compositions containing the compound described herein or derivatives thereof suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • compositions may also contain adjuvants, such as preserving, wetting, emulsifying, and dispensing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispensing agents.
  • Prevention of the action of microorganisms can be promoted by various antibacterial and antifungal agents, for example, parabens,
  • chlorobutanol phenol, sorbic acid, and the like.
  • Isotonic agents for example, sugars, sodium chloride, and the like may also be included.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration of the compounds described herein or derivatives thereof include capsules, tablets, pills, powders, and granules.
  • the compounds described herein or derivatives thereof is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example,
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art. They may contain opacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration of the compounds described herein or derivatives thereof include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,
  • oils in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.
  • additional agents such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.
  • Suspensions in addition to the active compounds, may contain additional agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • additional agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions of the compounds described herein or derivatives thereof for rectal administrations are optionally suppositories, which can be prepared by mixing the compounds with suitable non-irritating excipients or carriers, such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of the compounds described herein or derivatives thereof include ointments, powders, sprays, and inhalants.
  • the compounds described herein or derivatives thereof are admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic formulations, ointments, powders, and solutions are also contemplated as being within the scope of the compositions.
  • compositions can include one or more of the compounds described herein and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable salt refers to those salts of the compound described herein or derivatives thereof that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds described herein.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds described herein.
  • salts can be prepared in situ during the isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, methane sulphonate, and laurylsulphonate salts, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium,
  • pharmaceutically acceptable salts thereof can be carried out using therapeutically effective amounts of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein for periods of time effective to treat a disorder.
  • the effective amount of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein may be determined by one of ordinary skill in the art and includes exemplary dosage amounts for a mammal of from about 0.5 to about 200mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day.
  • the dosage amount can be from about 0.5 to about 150mg/kg of body weight of active compound per day, about 0.5 to lOOmg/kg of body weight of active compound per day, about 0.5 to about 75mg/kg of body weight of active compound per day, about 0.5 to about 50mg/kg of body weight of active compound per day, about 0.5 to about 25mg/kg of body weight of active compound per day, about 1 to about 20mg/kg of body weight of active compound per day, about 1 to about lOmg/kg of body weight of active compound per day, about 20mg/kg of body weight of active compound per day, about lOmg/kg of body weight of active compound per day, or about 5mg/kg of body weight of active compound per day.
  • the compounds described herein can be prepared in a variety of ways known to one skilled in the art of organic synthesis or variations thereon as appreciated by those skilled in the art.
  • the compounds described herein can be prepared from readily available starting materials. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art.
  • Variations on Formula I, Formula II, Formula III, and Formula IV include the addition, subtraction, or movement of the various constituents as described for each compound. Similarly, when one or more chiral centers are present in a molecule, the chirality of the molecule can be changed. Additionally, compound synthesis can involve the protection and deprotection of various chemical groups. The use of protection and deprotection, and the selection of appropriate protecting groups can be determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, which is incorporated herein by reference in its entirety.
  • Reactions to produce the compounds described herein can be carried out in solvents, which can be selected by one of skill in the art of organic synthesis. Solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products under the conditions at which the reactions are carried out, i.e., temperature and pressure. Reactions can be carried out in one solvent or a mixture of more than one solvent. Product or intermediate formation can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ⁇ ⁇ or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., ⁇ ⁇ or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • the methods include administering to a subject an effective amount of one or more of the compounds or compositions described herein, or a pharmaceutically acceptable salt or prodrug thereof.
  • effective amount when used to describe an amount of compound in a method, refers to the amount of a compound that achieves the desired pharmacological effect or other effect, for example, an amount that results in a reduction to radiation damage to tissue.
  • the compounds and compositions described herein or pharmaceutically acceptable salts thereof are useful for reducing or preventing radiation damage in humans, including, without limitation, pediatric and geriatric populations, and in animals, e.g., veterinary applications. Further described herein is a method for treating cancer in a subject.
  • the method includes administering to the subject an effective amount of ionizing radiation and then administering to the subject an effective amount of a compound or composition as described herein (e.g., a compound according to one or more of Formula I, Formula II, Formula III, Formula IV, DIM, or microencapsulated DIM).
  • a compound or composition as described herein (e.g., a compound according to one or more of Formula I, Formula II, Formula III, Formula IV, DIM, or microencapsulated DIM).
  • the compound according to one or more of Formula I, Formula II, Formula III, or Formula IV is microencapsulated.
  • the cancer is breast cancer, such as BRCAi -deficient breast cancer.
  • the cancer is ovarian cancer, such as BRCAi -deficient breast cancer.
  • the compound or composition can be administered to the subject before or after the subject has been exposed to radiation.
  • the compound or composition can be administered to the subject 1 minute or more, 2 minutes or more, 5 minutes or more, 10 minutes or more, 15 minutes or more, 30 minutes or more, 45 minutes or more, 1 hour or more, 2 hours or more, 3 hours or more, 4 hours or more, 5 hours or more, 10 hours or more, 15 hours or more, 20 hours or more, or 24 hours or more after exposure.
  • the compound or composition can be administered in multiple doses.
  • compositions and methods can include one or more additional agents.
  • the one or more additional agents and the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof can be administered in any order, including concomitant, simultaneous, or sequential administration. Sequential administration can be temporally spaced order of up to several days apart.
  • the methods can also include more than a single administration of the one or more additional agents and/or the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof.
  • the administration of the one or more additional agents and the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof can be by the same or different routes and concurrently or sequentially.
  • Therapeutic agents include, but are not limited to, chemotherapeutic agents and radioprotector compounds.
  • the therapeutic agent can, for example, be a chemotherapeutic agent.
  • a chemotherapeutic agent is a compound or composition effective in inhibiting or arresting the growth of an abnormally growing cell. Thus, such an agent may be used therapeutically to treat cancer as well as other diseases marked by abnormal cell growth.
  • Illustrative examples of chemotherapeutic compounds include, but are not limited to, Amifostine. Any of the aforementioned therapeutic agents can be used in any combination with the compositions described herein.
  • Combinations are administered either concomitantly (e.g., as an admixture), separately but simultaneously (e.g., via separate intravenous lines into the same subject), or sequentially (e.g., one of the compounds or agents is given first followed by the second).
  • combination is used to refer to concomitant, simultaneous, or sequential administration of two or more agents.
  • a therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein are administered to a subject prior to onset (e.g., before obvious signs of cancer or before radiation exposure), during early onset (e.g., upon initial signs and symptoms of cancer or radiation exposure), or after the development of cancer or exposure to radiation.
  • Prophylactic administration can occur for several days to years prior to the manifestation of symptoms of cancer or prior to radiation exposure.
  • Therapeutic treatment involves administering to a subject a therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein after cancer is diagnosed or radiation exposure is identified.
  • the methods and compounds described herein are also useful in killing a tumor cell and protecting a non-tumor cell.
  • the methods include irradiating the tumor cell with an effective amount of ionizing radiation and administering to the non-tumor cell an effective amount of a compound or composition as described herein.
  • the tumor cell is a BRCAi -deficient tumor cell.
  • the irradiating step can be performed prior to the administering step or the administering step can be performed prior to the irradiating step.
  • the method is performed in vivo.
  • the method is performed in vitro.
  • the methods herein for prophylactic and therapeutic treatment optionally comprise selecting a subject with or at risk of being exposed to radiation (e.g., military personnel or the civil population under a heightened security due to terrorist threats).
  • a subject with or at risk of being exposed to radiation e.g., military personnel or the civil population under a heightened security due to terrorist threats.
  • kits for reducing or preventing radiation damage in a subject or for treating cancer in a subject can include any of the compounds or compositions described herein.
  • a kit can include 3,3'-diindolylmethane (e.g.,
  • microencapsulated DIM a compound of Formula I, Formula II, Formula III, Formula
  • kits can further include one or more additional agents, such as anti-cancer agents (e.g., Amifostine).
  • a kit can include an oral or intraperitoneal formulation of any of the compounds or compositions described herein.
  • a kit can additionally include directions for use of the kit (e.g., instructions for treating a subject), a container, a means for administering the compounds or compositions (e.g., a syringe), and/or a carrier.
  • treatment refers to a method of reducing one or more symptoms of a disease or condition.
  • treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of one or more symptoms of the disease or condition.
  • a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms or signs (e.g., size of the tumor or rate of tumor growth) of the disease in a subject as compared to a control.
  • control refers to the untreated condition (e.g., the tumor cells not treated with the compounds and compositions described herein).
  • the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition.
  • prevent, preventing, and prevention of a disease or disorder refer to an action, for example, administration of a composition or therapeutic agent, that occurs before or at about the same time a subject begins to show one or more symptoms of the disease or disorder, which inhibits or delays onset or severity of one or more symptoms of the disease or disorder.
  • references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control (e.g., untreated) level. Such terms can include, but do not necessarily include, complete elimination.
  • subject means both mammals and non-mammals.
  • Mammals include, for example, humans; non-human primates, e.g., apes and monkeys; cattle; horses; sheep; rats; mice; pigs; and goats.
  • Non-mammals include, for example, fish and birds.
  • Example 1 DIM as a Radioprotector - Cultured Cells Studies
  • DIM a metabolite of indole-3-carbinol and a proposed cancer agent
  • DIM a potent radiation protector in cultured cells and in rodents (mice and rats).
  • the preparation of DIM that was used for most experiments was a microencapsulated form of DIM produced by BioResponse Nutrients (Boulder, CO).
  • This microencapsulated form of DIM is designed with specific excipients (e.g., alpha-tocopherol succinate and phosphatidylcholine) to provide enhanced absorption and, therefore, enhanced bioavailability.
  • DIM In cultured cells, both enhanced absorption DIM and crystalline DIM work very well as radioprotectors, but in animals, the enhanced absorption DIM is a better radioprotector than crystalline DIM, probably, in part, due to greater bioavailability.
  • DIM strongly protects against ionizing radiation (Cs-60 gamma radiation or high energy X-rays), based on rigorously performed clonogenic survival assays.
  • DIM in the absence of any DNA damage, appears to hyper-activate the cellular DNA damage-response machinery
  • DIM also stimulates the activity of DNA-dependent protein kinase (DNA-PK), another protein involved in the repair of double-strand DNA breaks.
  • DNA-PK DNA-dependent protein kinase
  • DIM-mediated radioprotection is observed at high doses of radiation as well as low doses (less that 200 cGy); thus DIM works throughout a wide spectrum of radiation doses. Fold-protection of different doses of DIM are in the range of 20 to 100-fold or higher. Data showing DIM radiation protection of cultured cells are provided in the attached grant proposals.
  • Example 2 DIM as a Radioprotector
  • DIM causes activation of ATM signaling without itself causing DNA damage.
  • MEFs BRCA1 -deficient mouse embryonic fibroblasts
  • wild-type MEFs were obtained.
  • 184A1 and Hs578Bst cells were cultured.
  • MCF-7 and T47D cells were grown in DMEM plus 5% fetal calf serum, 1-glutamine (5 mM), non-essential amino acids (5 mM), penicillin (100 U/ml), and streptomycin (100 ⁇ g/ml) (all obtained from BioWhittaker, Walkersville, MD).
  • BR-DIM 3,3'-diindolylmethane
  • subconfluent proliferating cells were irradiated with different doses of 137 Cs ⁇ -rays, harvested using trypsin, and plated at different densities in the absence or presence of DIM (as indicated) for colony formation (clonogenic survival) assays, as described in Zhang et al, Radiat Res, 161 :667-674 (2004). Values of surviving fraction are means ⁇ SEMs of triplicate plates.
  • Proliferating cells were treated with gene-specific siRNA or control-siRNA using siRNA Transfection Reagent (Santa Cruz Biotechnology, Santa Cruz, CA).
  • siRNA Transfection Reagent Santa Cruz Biotechnology, Santa Cruz, CA.
  • ATM-siRNA sc-29761
  • BRCAl-siRNA sc-29219
  • control-siRNA sc-37007
  • DNA strand rejoining assay DNA strand rejoining assay.
  • nuclear lysates were prepared and aliquots of lysate (50 or 75 ⁇ g of nuclear protein) were tested for their ability to rejoin a plasmid (pEGFP-1, Clontech) that had been linearized using restriction enzyme Smal.
  • the reaction products were detected by Southern blotting, which was performed with a digoxigenin-labeled enhanced green fluorescent protein R A probe.
  • the percent rejoined plasmids 98984 was determined by densitometric quantification of the bands corresponding to rejoined and unrejoined plasmid.
  • the primary antibodies were as follows: rabbit polyclonal anti-BRCAl (sc-642, Santa Cruz); mouse monoclonal cc-actin (sc-1616, Santa Cruz); anti-phospho-BRCAl (SI 387) [AB3257, Millipore (Billerica, MA)]; mouse monoclonal anti-ATM (sc-73615, Santa Cruz,); anti-phospho-ATM (S1981); anti-CHK2 (05- 649, mouse monoclonal, Millipore); anti-phosph-CHK2 (T68) (ab32055, rabbit monoclonal, Abeam, Cambridge, MA); anti-p53 (ab2433, rabbit polyclonal, Abeam), and rabbit polyclonal anti-phospho-p53 (SI 5) (ab38497, Abeam).
  • animal survival was plotted using Kaplan-Meier statistics; and the survival curves were compared using the log-rank test. Other statistical comparisons were made using two-tailed t-tests.
  • DIM very potently protects against very high (supra-lethal) doses of radiation: doses so high (e.g., 13-Gy) that, in the absence of DIM, none of the animals survive past 10-days.
  • Female Sprague-Dawley rats (age 12-16 weeks; weight 200 ⁇ 30 gm) were randomized into two groups of 30 animals each, one of which received 13-Gy 60 CO ⁇ - rays (0.96-Gy/min) as a single dose plus 0.1 -mL physiological saline intraperitoneally and the other of which received 13-Gy 60 CO ⁇ -rays plus DIM (7.5 mg/kg body weight, ip).
  • DIM was administered by intraperitoneal injection for convenience, but previous studies indicate excellent biodistribution when DIM (BR-DIM) is given orally.
  • DIM can be given to mice by oral gavage at 250 mg/kg with no toxicity and wide tissue distribution.
  • Figure 2a shows dose-dependent protection of Sprague-Dawley (SD) rats given once daily injections of DIM for 14-days starting 10-min after a 13-Gy dose of TBI.
  • SD Sprague-Dawley
  • DIM does not alter growth or radiosensitivity of MDA-MB-231 breast cancer xenografts
  • MDA-MB-231 human breast cancer cells were grown as xenograft tumors in the mammary fat pads of athymic nude mice.
  • the mice were either sham-treated or irradiated using a regimen of 5-daily treatments of 7-Gy each, for a total dose of 35-Gy.
  • the mice were given once daily injections of DIM (75 mg/kg) or vehicle for a total of six injections.
  • DIM had no effect on the growth of non-irradiated or irradiated tumors (Fig. 4a). Similar results were observed in a second experiment using a lower dose of radiation (20-Gy in 5-Gy fractions).
  • DIM activates ATM in normal tissues
  • DIM caused ATM phosphorylation by itself and enhanced the radiation-induced phosphorylation in normal rat kidney, liver, and brain (see Fig. 5).
  • Qualitatively similar results were observed in different tissues whether DIM was administered 24-hr before, 1-hr before, or 10-min after irradiation.
  • phospho-ATM levels were elevated at 24-hr after TBI, consistent with the idea that radiation causes ongoing oxidative stress in normal tissues, since most double-strand DNA breaks in irradiated cells are repaired within 2-3 hr.
  • Figs. 6a and 6b show the ability of DIM to protect two non-tumorigenic human mammary epithelial cell lines 184A1 and Hs578Bst.
  • Figs. 6c and 6d show the effect of DIM concentration on protection, using a single radiation dose (8-Gy).
  • DIM stimulates an ATM signaling pathway in cultured cells
  • DIM alone caused rapid activation of ATM, indicated by phosphorylation on serine-1981 in 184A1 cells (Fig. 7a) and other cell types.
  • phosphorylation was observed on two ATM substrates (BRCAl and CHK2) at the ATM sites on these proteins (Fig. 7a).
  • BRCAl and CHK2 two ATM substrates
  • KU55933, 10 ⁇ a selective ATM kinase inhibitor
  • MREl 1 is a component of the "MRN" (MREl 1-RAD50-NBS 1) complex, which is thought to act as a DNA damage sensor and up-stream activator of ATM.
  • MRN MRN
  • MREl 1 is a component of the "MRN" (MREl 1-RAD50-NBS 1) complex, which is thought to act as a DNA damage sensor and up-stream activator of ATM.
  • Individuals with MREl 1 mutations exhibit an ataxia-telangiectasia-like disorder (ATLD) similar to those with inherited ATM mutations.
  • ATLD2 and ATLD3 were more radiosensitive than CWAT and were not protected by DIM (Fig. lOa-c).
  • MREl 1 -deficient cells In contrast to wild- type fibroblasts (CWAT), MREl 1 -deficient cells (ATLD2) showed no DIM-induced phosphorylation of ATM or BRCAl after a 30 min exposure to DIM.
  • DIM stimulates DNA repair and inhibits apoptosis
  • the neutral comet assay is an electrophoretic method to measure DNA damage that reflects DSBs.
  • the percent of tail DNA after irradiation reflects the number of DSBs.
  • Pre-treatment with DIM (0.3 ⁇ ) for 24-hr reduced the % of comet tail DNA (reflecting DSBs) at 30-min and 2-hr post radiation (3-Gy), suggesting more rapid DNA repair (Figs. 1 1a and 1 lb).
  • a DNA strand-rejoining assay based on the ability of cell nuclei to rejoin a linearized plasmid (pEGFP-1) was also performed, detected by Southern blotting. This assay reflects the process of non-homologous end joining (NEHJ).
  • NSHJ non-homologous end joining
  • Fig. 1 lc nuclear extracts of vehicle- treated cells showed a modest ability to rejoin DNA strands that was greatly enhanced by pre- treatment with DIM.
  • KU55833 blocked DIM-induced strand-rejoining, suggesting it is ATM-dependent.
  • control cells gave 0-2% strand-rejoining and DIM- treated cells showed 40-60% rejoining.
  • Pre-treatment with DIM for 24-hr blocked radiation- induced apoptosis in 184A1 cells, as determined by flow cytometry of annexin V-labeled cells (Fig. l id).
  • the anti-apoptotic effect of DIM could also reflect ATM signaling, since ATM is known to stimulate anti- apoptotic pathways (eg., NF- ⁇ ) in irradiated cells.
  • Novel compounds were synthesized, which we have tested for their ability to protect cells against radiation in cultured cells. Some of these compounds gave strong levels of radiation protection similar to, slightly greater than, or slightly less than DIM, including compounds KED-4-157, KED-4-155, KED-4-159, KED-4-153, KED-4-123, KED-4-46, THW-5-85, and KED-4-69. None of these compounds are predicted to be free-radical scavengers or to be genotoxic. For reference, clonogenic radiation survival curves of cultured human mammary epithelial cells treated without or with DIM are shown in Figure 6, panels A and B.
  • human mammary epithelial cells at about 70-80% of confluency were treated with DIM (0.3 ⁇ ) or vehicle (DMSA) for 24 hours.
  • the cells were then irradiated using different doses of 137 Cs gamma rays, harvested, plated at different densities in the presence of DIM (0.3 ⁇ ) or vehicle, respectively, incubated for 14 days, and then counted for colony formation.
  • panels A and B the clonogenic survival curves are shown using non-tumorigenic human mammary epithelial cell lines Hs5788st (panel B) or 184A1 (panel A). All cell survival values are means ⁇ SEMs of three replicate dishes.
  • FIG. 13 A comparison of the survival enhancing effects of DIM against three different compounds is shown in Figure 13.
  • a single dose of radiation (8-Gy) was used and different concentrations of DIM (panel A), THW-5-85 (panel B), KED-4-155 (panel C), or KED-4- 157 (panel D).
  • Each analog was at least as potent as DIM at the different concentrations tested. Some analogs gave greater protection at some concentrations.
  • the mechanism of radiation protection is similar to that of DIM, but these compounds could also have other effects that are independent of DIM.
  • a combination of two of these agents gave considerably greater radiation protection than did either agent alone and also gave considerably greater radiation protection than did DIM, showing combination therapy may be more beneficial than single agent therapy.
  • These agents are of interest because they have the potential to make superior radioprotectors and mitigators to DIM. Although when used as single agents in cultured cells, the degree of protection is similar to that afforded by DIM, in combination they are superior to DIM. Importantly, when used in animals or humans, DIM is still limited by its bioavailability. Thus, an agent that is significantly more bioavailable than absorption enhanced DIM (BR- DIM) makes a superior radioprotector and/or radiation mitigator in animals and humans even though at the cellular level it is only as good as DIM.
  • BR- DIM absorption enhanced DIM

Abstract

L'invention concerne des composés radioprotecteurs comprenant des analogues de 3,3'- diindolylméthane (DIM). L'invention concerne en outre des procédés pour leur utilisation destinés à réduire ou à prévenir des lésions dues à un rayonnement, à supprimer une cellule tumorale et à protéger une cellule non tumorale, et à traiter le cancer.
PCT/US2013/031385 2012-03-16 2013-03-14 Composés radioprotecteurs WO2013138600A1 (fr)

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